CN102432986B - Biodegradable particle - Google Patents

Biodegradable particle Download PDF

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Publication number
CN102432986B
CN102432986B CN201110265699.0A CN201110265699A CN102432986B CN 102432986 B CN102432986 B CN 102432986B CN 201110265699 A CN201110265699 A CN 201110265699A CN 102432986 B CN102432986 B CN 102432986B
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particle
biodegradable
weight
water
conduit
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CN102432986A (en
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棚桥一裕
中西惠
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Toray Industries Inc
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Toray Industries Inc
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/14—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L31/148—Materials at least partially resorbable by the body
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
    • A61L24/001—Use of materials characterised by their function or physical properties
    • A61L24/0042—Materials resorbable by the body
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
    • A61L24/04—Surgical adhesives or cements; Adhesives for colostomy devices containing macromolecular materials
    • A61L24/046—Surgical adhesives or cements; Adhesives for colostomy devices containing macromolecular materials obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/04—Macromolecular materials
    • A61L31/06—Macromolecular materials obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/04—Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
    • C08J3/00—Processes of treating or compounding macromolecular substances
    • C08J3/12—Powdering or granulating
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
    • C08L67/00—Compositions of polyesters obtained by reactions forming a carboxylic ester link in the main chain; Compositions of derivatives of such polymers
    • C08L67/04—Polyesters derived from hydroxycarboxylic acids, e.g. lactones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2430/00—Materials or treatment for tissue regeneration
    • A61L2430/36—Materials or treatment for tissue regeneration for embolization or occlusion, e.g. vaso-occlusive compositions or devices
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
    • C08J2367/00—Characterised by the use of polyesters obtained by reactions forming a carboxylic ester link in the main chain; Derivatives of such polymers
    • C08J2367/04—Polyesters derived from hydroxy carboxylic acids, e.g. lactones
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
    • C08L71/00—Compositions of polyethers obtained by reactions forming an ether link in the main chain; Compositions of derivatives of such polymers
    • C08L71/02—Polyalkylene oxides

Abstract

The present invention aims to provide a biodegradable particle capable of being molded without an aggregation or cohesion of the particles, capable of being carried or injected without clogging by an aggregation in a micro diameter tube such as of a catheter, needle or syringe mainly used in pharmaceutical and medical applications of which inner diameter is smaller than the particle size or in a blood vessel and capable of being smoothly degraded in a specified period of time so that degraded component can finally be absorbed or discharged in vitro. As means for solving the problem, the present invention provides a biodegradable particle characterized in that a compressive modulus of the particle in water saturated state is 10 MPa or less.

Description

Biodegradable particle
The application is to be the divisional application of the application that October 26, application number in 2006 are 200680037430.4, denomination of invention is " Biodegradable particle and manufacture method thereof " applying date.
Technical field
The present invention relates to a kind of biological degradability spherical particle, described particle transports by micro-small-bore pipes that have, that be less than size of particles such as the main conduit as medical medical device, pin, syringes.
Background technology
At medical field, the viewpoint of start gradually to pay attention to the security for the treatment of, patient not being made cumbrous low invasion and attack treatment.The synthetic safer technology of material and the technology of vivo medicine-feeding of design grows up thereupon.One of them is to treat or the technology of administration by small-bore pipe.Because the bore of pipe is little, so needn't cut patient's health, the pain causing in pipe insertosome is also die-offed.The treatment that uses conduit to carry out is its significant example.Another is the technology about absorbent material in not residual biological degradation gonosome in vivo.The suture line being made up of poly(lactic acid) or polyglycolic acid, polycaprolactone etc. or orthopaedic materials have also been applied to clinical, recently, have also reported in a large number the achievement in research of applying above-mentioned raw-material regenerative medicine.The known polymer particle being degraded and absorbed in vivo is mainly used as the carrier (referring to patent documentation 1,2) of medicine.
In addition, before the organ operations such as liver cut, embolism materials is injected in blood vessel, can really and promptly stop blooding, by the hemorrhage bottom line of being down to.As the technology, the therapy that use this embolism materials, except for preventing hemorrhage purposes, become known for tumour to excising and block the purposes of arterial embolization of nutrition and combination by hemostasis and give carcinostatic agent and vascular suppository material the carcinostatic agent concentration in tumour is maintained the chemoembolization therapy of higher level.On the other hand, along with the development of conduit and operation technique thereof, suitable carrier particles or embolism materials optionally accurately can be transported to part.
As vascular suppository material, use at present gelfoam, polyvinyl alcohol, degradation property starch particle (DSM), iodate seed of Papaver somniferum L. powder, crosslinked with collagen fiber, ethyl cellulose microcapsule, cyanoacrylate, stainless steel coi etc.Wherein, the embolism materials being made up of polymer particle can, to be scattered in the state in contrast medium etc., via configuration microtubular in vivo, to be injected and import in body towards affected part by micro-syringe etc.The embolism materials of above-mentioned polymer particle can arrive the affected part formation embolism that is positioned at deep.
But there is following problems in the carrier particles or the embolism materials that are made up of polymer particle.
(1) be shaped as amorphous, size-grade distribution is wide, so sometimes do not bring into play its function at target site.
(2) aggegation sometimes (aggregation) or high viscosity and stop up in the pipe of the medical medical devices such as conduit, pin or syringe.Particularly often stop up when than the little particle of the internal diameter of conduit.
(3) owing in the normal blood vessels midway that arrives affected part, aggegation or high viscosity occurring, so sometimes cannot make it arrive target site.
(4) while use as embolism materials, because material is hard, do not meet the section form of blood vessel, reduce so sometimes allow to volume of blood flow, also embolism completely.
(5) and, as biological degeneration material, the position of contact blood with the position etc. that does not contact blood sometimes because the fine difference of environment of living in causes degradation speed bigger difference.
(6) due to particle diameter inappropriate, so sometimes cannot be retained in target site.
(7) be particularly less than the particle of catheter diameter, after conduit, do not recover original shape, just directly transported to affected part with broken state, so sometimes form embolism at wide portion bit position.
As prior art, the particle (referring to non-patent literature 1) being made up of the poly(lactic acid) as Biodegradable polymer (hereinafter referred to as PLA) or poly-(lactic acid/oxyacetic acid) multipolymer (hereinafter referred to as PLGA), the Biodegradable material (referring to patent documentation 3) that contains certain drug are disclosed, but, because the hydrophobicity of substrate polymer is high, there is the problem of above-mentioned (2)～(5) in above-mentioned substance.
On the other hand, disclose hybrid medicine in substrate polymer and made its application of the technology slowly discharging in pharmacy veterinary drug purposes, described substrate polymer forms (referring to patent documentation 4) by the structure such as PLA-PEG, PLA-PEG-PLA, PLGA-PEG-PLGA of the segmented copolymer as by polyoxyethylene glycol (hereinafter referred to as PEG) and PLA or PLGA formation.But above-mentioned technology is difficult to adjust flexibility and the required intensity of moulding of substrate polymer, has the arbitrary problem in above-mentioned (1)～(5).
In addition, the vascular suppository material (patent documentation 5) being made up of water-insoluble PEG analog copolymer is disclosed.But above-mentioned materials is also difficult to adjust flexibility and the required intensity of moulding of substrate polymer, has the arbitrary problem in above-mentioned (1)～(5) and (7).
The technology of stopping up occurs when above-mentioned Biodegradable particle being transported by injecting from conduit as improvement in conduit, and the modulus in tension that discloses film is the particle (patent documentation 6) that 1500MPa is following, be made up of insoluble polymers such as polyoxyethylene glycol analog copolymers.But, above-mentioned disclosed technology is as shown in the embodiment of the document, just improve the technology that size of particles is less than the conduit trafficability characteristic of the particle of catheter diameter, be not the invention that is greater than the trafficability characteristic of the particle of catheter diameter for improving diameter, prevent that diameter is greater than the molecular weight ranges or the composition etc. that in the conduit that the particle of catheter diameter causes, stop up required multipolymer so do not provide.
And then patent documentation 5,6 is not mentioned the problem relating to by (7) of Postductal Restoration completely, do not provide the molecular weight ranges or the composition etc. that restore required multipolymer yet.
Patent documentation 1: No. 3242118 communique of patent
Patent documentation 2: No. 3428972 communique of patent
Patent documentation 3: Unexamined Patent 5-969 communique
Patent documentation 4: JP 5-17245 communique
Patent documentation 5: JP 2004-167229 communique
Patent documentation 6: JP 2004-313759 communique
Non-patent literature 1:BastianP (Bastian P), the work such as BartkowskiR (Bartkowski R), " Chemo-embolizationofexperimentallivermetastases (Chemo-embolization of experimental liver metastases.) ", EuropeanJournalofPharmaceuticsandBiopharmaceutics (European Journal of Pharmaceutics and Biopharmaceutics), 1998, the 43rd volume, p243-254.
Summary of the invention
The object of the present invention is to provide a kind of spherical particle of biological degradability, described particle has at the utensil such as conduit or pin, syringe that is mainly used in medical medical use, internal diameter is less than in the micro-small-bore pipe of described size of particles or aggegation does not occur in blood vessel and stops up, and can recover original shape after in managing, after between given period, material is degraded smoothly, and degraded composition finally can be absorbed or be discharged to external.
1. a Biodegradable particle, is characterized in that, the compressive modulus of elasticity of the particle under saturated aqueous state is below 10MPa.
2. a Biodegradable particle, it is characterized in that, described Biodegradable particle has base material, and described base material contains water-soluble polymers and Biodegradable polymer, and described water-soluble polymers is 0.60～0.70 with respect to the content ratio of described Biodegradable polymer.
3. the Biodegradable particle as described in above-mentioned 2, is characterized in that, described Biodegradable particle has degradation property in the phosphate buffer normal saline of 37 DEG C.
4. the Biodegradable particle as described in above-mentioned 2 or 3, it is characterized in that, the median size of described Biodegradable particle is more than 100 μ m, and the Postductal particle diameter more than 60%, below 85% that 'go'gage is its particle diameter under saturated aqueous state is greater than the bore of described conduit.
5. the Biodegradable particle as described in any one in above-mentioned 2～4, is characterized in that, the compressive modulus of elasticity of the particle under saturated aqueous state is below 10MPa.
6. the Biodegradable particle as described in any one in above-mentioned 1～5, is characterized in that, described water-soluble polymers is polyalkylene glycol or derivatives thereof.
7. the Biodegradable particle as described in above-mentioned 6, is characterized in that, the weight-average molecular weight of this polyalkylene glycol is more than 200, below 40,000.
8. a Biodegradable particle, is that particle diameter is particle more than 5 μ m, it is characterized in that, described particle is by the coating of polyalkylene glycol or derivatives thereof.
9. the Biodegradable particle as described in above-mentioned 1～7, is characterized in that, described particle is by the coating of polyalkylene glycol or derivatives thereof.
10. the Biodegradable particle as described in above-mentioned 8 or 9, is characterized in that, the weight-average molecular weight of described polyalkylene glycol is more than 1,000, below 40,000.
11. Biodegradable particles as described in any one in above-mentioned 6～10, is characterized in that, described polyalkylene glycol is polyoxyethylene glycol.
12. Biodegradable particles as described in any one in above-mentioned 1～11, is characterized in that, the particle diameter of described particle is 5～2000 μ m.
13. Biodegradable particles as described in any one in above-mentioned 1～12, is characterized in that, the size-grade distribution of described particle median size ± 60% in.
14. Biodegradable particles as described in above-mentioned 12 or 13, is characterized in that, described particle is spherical.
15. Biodegradable particles as described in any one in above-mentioned 2～14, is characterized in that, described Biodegradable polymer contains alpha hydroxy acid unit.
16. Biodegradable particles as described in above-mentioned 2～15, is characterized in that, the weight-average molecular weight of the water-insoluble copolymer being made up of described water-soluble polymers and described Biodegradable polymer is 1,000～100,000.
17. Biodegradable particles as described in any one in above-mentioned 1～16, is characterized in that, described Biodegradable particle is used to medical medical use.
18. Biodegradable particles as described in above-mentioned 1～16, is characterized in that, described Biodegradable particle is used as intracorporeal indwelling utensil.
19. Biodegradable particles as described in above-mentioned 18, is characterized in that, described Biodegradable particle is used to embolotherapy.
The manufacture method of 20. 1 kinds of Biodegradable particles, it is characterized in that, under fusion saturated aqueous state, there is the insoluble polymer B under the insoluble polymer A of modulus in tension of the film of the above and not enough 50MPa of 1MPa and saturated aqueous state with the modulus in tension of film more than 50MPa, obtain particle.
The manufacture method of 21. Biodegradable particles as described in above-mentioned 20, is characterized in that, the mix proportions of described insoluble polymer B is more than 20 % by weight.
The manufacture method of 22. 1 kinds of Biodegradable particles, it is the manufacture method of the Biodegradable particle that obtained by water-soluble polymers and Biodegradable polymer, it is characterized in that, the weight ratio of fusion water-soluble polymers is the insoluble polymer D of the weight ratio less than 50% of more than 50% insoluble polymer C and water-soluble polymers, obtains particle.
The manufacture method of 23. Biodegradable particles as described in above-mentioned 22, is characterized in that, the mix proportions of described insoluble polymer D is more than 20 % by weight.
The manufacture method of 24. Biodegradable particles as described in any one in above-mentioned 20～23, is characterized in that, described insoluble polymer is the multipolymer that water-soluble polymers and Biodegradable polymer chemical bonding form.
25. Biodegradable particles as described in any one in above-mentioned 1 or 19, is characterized in that, described Biodegradable particle is that the manufacture method of the Biodegradable particle described in any one adopting in above-mentioned 20～24 is manufactured.
As described below, a kind of particle can be provided according to the present invention, described particle has at utensils such as being mainly used in the conduit of medical medical use, pin, syringe, internal diameter is less than in the pipe of described size of particles or in blood vessel, does not cause that aggegation stops up, and can recover original shape after in managing, no matter how are indwelling position or indwelling environment, after between given period, all degradeds smoothly in vivo, degraded composition finally can be absorbed or be discharged to external.
Embodiment
Biodegradable particle in the present invention refers to the particle of degrading under the effect of the enzyme of the chemical degradation to be hydrolyzed to representative or cell or microorganisms.The main particle being preferably hydrolyzed.Raw material to used Biodegradable particle is not particularly limited, it can be natural polymer, any in the polymkeric substance of synthetic, there is polyester, polyethers, poly-acid anhydrides, polypeptide, poly-(α-cyanoacrylate), polyacrylamide, poly-(ortho ester), polyphosphonitrile, polyamino acid, biological degradation based polyurethane, polycarbonate, poly-iminocarbonic ester, nucleic acid, polyose etc., as concrete typical example, can enumerate gelatin, chitin, chitosan, dextran, Sudan Gum-arabic, alginic acid, starch, poly(lactic acid) (hereinafter referred to as PLA), polyglycolic acid (hereinafter referred to as PGA), PLGA (hereinafter referred to as PLGA), C-terminal gathers (6-caprolactone)-polyethers, polycaprolactone, normal-butyl alpha-cyanoacrylate and multipolymer of being formed by above-mentioned polymkeric substance etc.
As the first scheme of Biodegradable particle of the present invention, preferably have elasticity in the micro-small-bore pipe that 'go'gage is easily less than described size of particles and can be in conduit, keep the material of necessary intensity in blood vessel etc., therefore the compressive modulus of elasticity under saturated aqueous state can be below 10MPa, more than being preferably 0.5MPa, below 10MPa, more preferably below 5MPa, more preferably below 3MPa.Said saturated aqueous state refers to that the water ratio that is immersed in the material in normal temperature pure water reaches stable state herein.It should be noted that,, refer to that certain material process its changes in weight of a few hours is still in 3% even if water ratio is stable herein.The material that compressive modulus of elasticity under saturated aqueous state exceedes 10MPa is harder, is not suitable for use in having the material that microtubular that internal diameter is less than the pipe of the particle diameter of Biodegradable particle etc. gives to be used.
Elastic properties for example can be evaluated as described below.
[condition determination]
Compression testing machine: MCT-W500; (strain) Shimadzu Seisakusho Ltd. system (or also can be used the device that can obtain identical result under the same terms.)
Testing laboratory's temperature: 25 DEG C
Testing laboratory's humidity: 50%
Top pressurization pressure head: flush type φ 500 μ m
Load speed: 4.462mN/sec
For the stress-strain curve that adopts aforesaid method to obtain, can obtain compressive modulus of elasticity by following formula.
Compressive modulus of elasticity (unit: MPa)=(δ 2-δ 1)/(ε 2-ε 1)
Herein, strain stress 1=0.0005, strain stress 2=0.0025.δ 1, δ 2 are stress under compressiones corresponding to ε 1, ε 2 of being determined uniquely by stress-strain curve.
In the present invention, can be easily by the soft elasticity in micro-small-bore pipe in order to show, preferably at least 2 kinds of different insoluble polymers of fusion modulus in tension.Particularly, preferably the insoluble polymer of constituent particle has film forming ability, the modulus in tension of the film of a kind of polymkeric substance (polymer A) that forms this insoluble polymer under saturated aqueous state is more than 1MPa, not enough 50MPa, another kind of polymkeric substance (polymer B) be 50MPa above, below 400MPa.And, in order to ensure necessary intensity, more than the ratio of polymer B most preferably is 20 % by weight.The Young's modulus that the particle of manufacturing by above-mentioned fusion has is not controlled the getable Young's modulus of composition of single polymers.
The modulus in tension of the film in the present invention is one of tensile properties of film, the tensile properties of the film of what is called of the present invention under saturated aqueous state refer to the film being obtained by the insoluble polymer with film forming ability is reached to water ratio in pure water in normal temperature dipping stable after, measure the characteristic value such as Young's modulus, degree of stretching obtaining.It should be noted that, refer to that certain material process a few hours its changes in weight still 3% in even if water ratio is stable herein.
The tensile properties of film for example can be evaluated as described below, also can adopt the evaluation method that can obtain result equal with it.It should be noted that, as film, have teeming practice, excellent Tu Fa etc., the modulus in tension in the present invention is measured and is obtained the film that adopts teeming practice to form.
[condition determination]
Tensile testing machine: RTM-100 type; (strain) Orientec system (or also can be used the device that can obtain identical result under the same terms.)
Testing laboratory's temperature: 25 DEG C
Testing laboratory's humidity: 50%
Test film shape: rectangle (80mm × 7.5mm)
Test film thickness: 30 μ m ± 10 μ m
Chuck spacing: 20mm
Trial speed: 10mm/ minute
It should be noted that, in Biodegradable particle of the present invention, except at least 2 kinds of different polymkeric substance of above-mentioned modulus in tension, also can add following other compositions, i.e. oil contrast media, effective component etc.
To the shape of Biodegradable particle of the present invention, there is no particular limitation, while particularly considering the medical medical use taking human body as object, preferably at 37 DEG C, keeps particle shape, more preferably spherical particle.When said spherical particle refers to from any one direction using particle as round observation herein, the maximum perpendicular length of circle internal diameter is more than 0.5 below 1.0 with respect to the ratio of maximum length, preferably more than 0.8 particle in 1.0 following scopes, not only comprise ball shape, also comprise the shape such as spheroid, oblate spheroid of olive ball-type.In addition, when particle of the present invention does not keep particle shape for liquid state, gel etc. at 37 DEG C, because intensity is low, so possibly cannot be retained in target site.On the other hand, as long as keeping the particle of spherical shape, just more effectively indwelling is in vivo and bring into play objective function.
Biodegradable particle of the present invention preferably has the particle of degradation property in the phosphate buffer normal saline of 37 DEG C, because have above-mentioned characteristic, so can be for medical medical use, particularly indwelling to the embolism materials purposes in body.
In the present invention, in the phosphate buffer normal saline of 37 DEG C, have degradation property refer in the phosphate buffer normal saline of 37 DEG C dipping certain during after the dry weight of particle or the weight-average molecular weight of the polymkeric substance of constituent particle be reduced to before dipping below 80%.Time to dipping is not particularly limited, and also can after long-time, degrade.
In addition, the characteristic relating to as the alternative plan of Biodegradable particle of the present invention, preferably median size is more than 100 μ m, and in the time of saturated aqueous state, 'go'gage also keeps above-mentioned preferred spherical shape (spherical), i.e. " the maximum perpendicular length of circle internal diameter is the shape in the scope more than 0.8, below 1.0 with respect to the ratio of maximum length " after being less than in the micro-small-bore pipe of mentioned particulate size without resistance.Particularly preferably 'go'gage size also keeps spherical after in the micro-small-bore pipe more than 60%, below 85% of particle diameter.By in above-mentioned micro-small-bore pipe time, there is the distortion more than 15%, below 40% of its particle diameter in Biodegradable particle in compressed direction.Therefore, Biodegradable particle of the present invention has and is compressed load and while there is above-mentioned distortion, only need discharges and can recover spherical characteristic, preferably reverts to original shape.During especially for embolism materials purposes because conduit is thinner than the blood vessel of embolism, so particle must have just just can vascular embolization by conduit shape.Therefore, for the Biodegradable particle under saturated aqueous state, preferably in the time making in the conduit more than 60%, below 85% that above-mentioned Biodegradable particle 'go'gage is its particle diameter, without applying any peripheral operation, by after the particle diameter of above-mentioned Biodegradable particle just naturally reach pipe aperture more than.
In addition, even if said saturated aqueous state refers to that the material being immersed in normal temperature pure water passes through the also state in 3% of changes in weight of its water ratio of a few hours herein.
; for example, during for blood vessel embolism purposes, use microtubular etc. to give in blood vessel, under the state of the saturation state that reaches capacity because of the moisture in blood, cannot keep spherical particle because the particle diameter of specific direction diminishes; therefore very likely at wide portion bit position embolism, unsatisfactory.
The formation of the alternative plan of Biodegradable particle of the present invention is the Biodegradable particle with base material, above-mentioned base material contains water-soluble polymers and Biodegradable polymer, and water-soluble polymers is 0.60～0.70 with respect to the ratio that contains of this Biodegradable polymer.Water-soluble polymers is less than at 0.60 o'clock with respect to the ratio that contains of this Biodegradable polymer, flexibility deficiency while being particularly shaped to particle, and the particle that diameter is greater than catheter diameter cannot pass through conduit.In addition, exceed at 0.70 o'clock, by not returning to the original form after conduit, cannot obtain Restoration.The content of water-soluble polymers and Biodegradable polymer can be by measuring 1h-NMR is determined.Particularly, obtain its content by the quantity of hydrogen atom and the molecular weight of repeating unit that comprise in the integrated value of the signal of the chemical shift of the proton from water-soluble polymers and Biodegradable polymer characteristic chemical structure separately, repeating unit.Be for example in the situation by polyoxyethylene glycol and the water-insoluble copolymer of poly-(lactic acid-ethanol) multipolymer formation, relative integral value from the signal of the chemical shift 3.4-3.7ppm of 4 hydrogen atoms of the ethylidene of polyoxyethylene glycol is A, relative integral value from the signal of the chemical shift 1.4-1.6ppm of 3 hydrogen atoms of the methyl of lactic acid units is B, while being C from the relative integral value of the signal of the chemical shift 4.7-4.9ppm of 2 hydrogen atoms of the methylene radical of oxyacetic acid unit, use the molecular weight 44 of each repeating unit, 72, 58, the content of polyoxyethylene glycol represents with following formula.
Content (%)=100 × (44 × A/4)/((44 × A/4)+(72 × B/3)+(58 × C/2))
In addition, the compressive modulus of elasticity of the particle of such scheme of the present invention is preferably below 10MPa, and in order to show above-mentioned characteristic, preferably at least 2 kinds of different insoluble polymers of fusion modulus in tension are insoluble polymer A and polymer B.
As the prilling process of particle, can adopt rotation comminution granulation, fluidised bed comminution granulation, a spraying layer comminution granulation, stirring-granulating method, pulverize the known methods such as comminution granulation, compression comminution granulation, extruding pelletization method, the curing comminution granulation of drop.For example; while adopting drop to solidify comminution granulation; can manufacture as follows: insoluble polymer is dissolved in methylene dichloride, chloroform, ethyl acetate or isopropyl ether etc.; be dispersed in the water that contains tensio-active agent, protective colloid agent etc., utilize known oil/water type (hereinafter referred to as O/W type) or water/oil/water type (hereinafter referred to as W/O/W type) intra-liquid desiccation method or the method such as method, spray-drying process based on aforesaid method to become particle shape.As tensio-active agent used herein, protective colloid agent; as long as forming the material of stable O/W type emulsion; be not particularly limited, for example, can enumerate anionic surfactant's (sodium oleate, sodium stearate, Sodium Lauryl Sulphate BP/USP etc.), nonionic surfactant (polyoxyethylene sorbitan fatty acid ester, castor oil derivatives etc.), polyvinyl alcohol, Polyvinylpyrolidone (PVP), carboxymethyl cellulose, Yelkin TTS, gelatin etc.Wherein, can use a kind or be used in combination multiple.Particularly preferably polyvinyl alcohol, carboxymethyl cellulose, gelatin.Its concentration of aqueous solution is selected in the scope of 0.01～80 % by weight, more preferably in the scope of 0.05～60 % by weight, selects, and can adjust particle shape and/or particle diameter by adjusting its concentration.In addition, also can easily adjust particle shape or particle diameter by the polymer concentration of adjusting insoluble polymer lysate.Adopt the particle of above-mentioned manufacture method manufacture to be generally spherical particle, but comprise the particle of various particle diameters.For the particle that obtains thering is target grain size, targeted particle size distributes, can use multiple sieves.Multiple sieves are started overlapping successively from the little sieve of mesh, on the sieve of the top of mesh maximum, drop into and be dispersed with the liquid that adopts the particle that above-mentioned manufacture method makes, particle is stayed on the sieve that mesh size is less than particle diameter, so particle can be separated by particle diameter.The mesh size of sieve is not particularly limited, and according to target particle diameter and size-grade distribution are suitably selected.
The particle diameter of Biodegradable particle of the present invention is preferably 5～2,000 μ m, more preferably 10～1,500 μ m.When Biodegradable particle is used as to carrier particles, if particle diameter in above-mentioned scope, can pass through the successfully indwellings such as conduit, pin or syringe in body, in target site performance function, so preferably.In addition, by Biodegradable particle, when the embolism purposes, if in above-mentioned scope, embolism target site effectively, so preferably.When the such use, its size-grade distribution be preferably median size ± below 60%, more preferably median size ± below 50%.
In the present invention, particle diameter, median size, size-grade distribution refer to particle diameter, median size, the size-grade distribution in pure water or the physiological saline of 25 DEG C.The median size of particle of the present invention and size-grade distribution can be used commercially available various determinators to measure, while particularly using Leeds & Northrup society (strain) particle size distribution device processed " Microtrac series ", can in physiological saline, measure, so consider preferably this device from can carry out mensuration under the state that approaches blood vessel or internal milieu aspect.Or also can adopt the device that can obtain equal with it result.Median size is calculated by volume averaging value, and " Microtrac series " does not consider the sphericity of particle, with " MV " value representation.
The multipolymer that insoluble polymer of the present invention is preferably obtained by water-soluble polymers and Biodegradable polymer chemical bonding forms.In the present invention said water-soluble polymers refer to and add polymkeric substance to water with the concentration below saturation concentration under normal pressure in time, the amount of interpolation is all dissolved, and obtains the polymkeric substance of homogeneous solution.Required time, the temperature of polymer dissolution is not particularly limited.In addition, insoluble polymer refers to the polymkeric substance outside the definition of above-mentioned water-soluble polymers.By controlling water-soluble polymers in above-mentioned multipolymer and the ratio of Biodegradable polymer, can prepare respectively above-mentioned insoluble polymer A and insoluble polymer B, the above-mentioned polymkeric substance of fusion obtains Biodegradable particle of the present invention.Concrete ratio is not particularly limited, and preferably in fusion insoluble polymer, the shared weight ratio of water-soluble polymers is more than 50% insoluble polymer C and the water-insoluble copolymer D of weight ratio less than 50%.And in order to ensure essential intensity, most preferably the ratio of polymkeric substance D is more than 20 % by weight.
In addition, as above-mentioned water-soluble polymers, preferably use polyalkylene glycol.The water-insoluble copolymer that uses above-mentioned water-soluble polymers is that water-insoluble polyalkylene glycols multipolymer refers to the segmented copolymer taking polyalkylene glycol or derivatives thereof as a kind of composition wherein etc.Also can be by interacting and the thawless multipolymer of water with polyalkylene glycol or derivatives thereof generation physical property.As polyalkylene glycol, can enumerate polyoxyethylene glycol (hereinafter referred to as PEG), polypropylene glycol, most preferably there is organism adaptability, be applied to the PEG in medical medical use.The water-insoluble PEG analog copolymer particularly preferably being obtained by PEG or PEG derivative and Biodegradable polymer chemical bonding forms, be not particularly limited, preferably use two ends of PEG or a side end chemical bonding to have the multipolymer of Biodegradable polymer or PEG and Biodegradable polymer to replace the multipolymer that bonding forms.
In addition, Biodegradable polymer refers to the polymkeric substance of degrading under the effect of the enzyme of the chemical degradation to be hydrolyzed to representative or cell, microorganisms herein.The kind of above-mentioned Biodegradable polymer is not particularly limited, and preferred polyester, polyose, polypeptide etc. most preferably contain the polymkeric substance of alpha hydroxy acid unit.As the examples of polymers that contains alpha hydroxy acid unit, can enumerate poly(lactic acid), polyglycolic acid.Be not particularly limited having as above-mentioned Biodegradable polymer with the raw material of the Biodegradable polymer of the character of PEG or PEG derivatives chemical bonding, can enumerate lactic acid, oxyacetic acid, 2-hydroxybutyric acid, 2-hydroxypentanoic acid, 2-hydroxycaproic acid, 2-hydroxydecanoic acid, rac-Lactide, glycollide, oxysuccinic acid etc., more than preferably containing any in above-mentioned substance, more preferably be used in combination two or more and form multipolymer, particularly preferably the combination of lactic acid (or rac-Lactide) and oxyacetic acid (or glycollide).Now, the weight ratio of lactic acid and oxyacetic acid be preferably 100: 0～30: 70.It should be noted that, in above-claimed cpd, in the quasi-molecule of lactic acid or rac-Lactide, having optically active compound can be D body, L body, D, any in the mixture of L body, D body and L body.
It is 1,000～100,000 that the preferred core part of Biodegradable particle of the present invention contains weight-average molecular weight, be preferably 2,000～90,000 water-insoluble copolymer, for example water-insoluble polyalkylene glycols multipolymer.If weight-average molecular weight less than 1,000, is gel, stick to the surface of the pipe of conduit or pin, sometimes cannot arrive target site; And if weight-average molecular weight exceedes 100,000, sometimes particle degrade in vivo consume overlong time.
In addition, the weight-average molecular weight of above-mentioned polyalkylene glycol or derivatives thereof is preferably 200～40, and 000.If be less than 200, the wetting ability of polyalkylene glycols multipolymer is low, sometimes cannot obtain uniform biological degradability.And if be greater than 40,000, the polyalkylene glycol being generated by the multipolymer of degrading is in vivo difficult to be discharged to external sometimes.In addition, the structure of polylalkylene glycol derivatives is not particularly limited, and can preferably use the material of the structure that also comprises multi-arm (multi-arm) polylalkylene glycol derivatives.The weight ratio of polyalkylene glycol or derivatives thereof and Biodegradable polymer is not particularly limited, and can more preferably use the scope of 80: 20～5: 95.
Below, as the typical example of the manufacture method of insoluble polymer of the present invention, enumerate the manufacture method of the water-insoluble polyalkylene glycols multipolymer being formed by polyalkylene glycol or polylalkylene glycol derivatives and Biodegradable polymer.Method for the synthesis of water-insoluble polyalkylene glycols multipolymer is not particularly limited, and can enumerate melt polymerization, ring-opening polymerization etc.For example, in dry air or dry nitrogen air-flow, in the polymerization tank that stirring rake is installed, drop into water-soluble polymers (polyalkylene glycol or polylalkylene glycol derivatives) and the Biodegradable polymer raw material (monomer etc.) as the specific molecular-weight average of raw material, said mixture and catalyzer are together stirred, heat simultaneously, obtain thus water-insoluble multipolymer.The catalyzer of the catalyzer using as long as using in common polyester, is not particularly limited.For example can enumerate the tin halides such as tin chloride, the organic acid tin such as 2 ethyl hexanoic acid tin, the organic alkali metal compounds such as zinc ethyl, zinc lactate, ironic lactate, dimethyl aluminium, hydrolith, butyllithium or potassium tert.-butoxide, the metal alkoxides such as metalloporphyrin coordination compound or diethyl aluminum methylate etc.In addition, also can use twin shaft mixing extruder or the similar device with stirring and feed function with ventilating pit, by Biodegradable polymer raw material, polyalkylene glycol or polylalkylene glycol derivatives and catalyzer stirring under molten state, mixing, degassed, take out continuously the insoluble polymer generating simultaneously, carry out polymerization.And, also the insoluble polymer of generation can be dissolved in good solvent, splash into therein poor solvent, generate after precipitation, the temperature that changes white casse thing, after throw out is dissolved again, more slowly returns to original temperature, regeneration precipitation, improves fractionation precision by above-mentioned redeposition.As the good solvent using in above-mentioned step-by-step precipitation method, for example, can enumerate tetrahydrofuran (THF) or halogen class organic solvent (methylene dichloride, chloroform) or their mixed solvent.As the poor solvent using in above-mentioned step-by-step precipitation method, the preferably organic solvent of alcohols or hydro carbons.By the kind of suitable selection Biodegradable polymer and water-soluble polymers and their molecular weight, can prepare multiple water-insoluble polyalkylene glycols multipolymer.
Aforesaid method, taking water-insoluble polyalkylene glycols multipolymer as example, also can use polymethyl acrylic acid hydroxyl methyl esters, vinylformic acid, methacrylic acid, Polyvinylpyrolidone (PVP) etc. to replace polyalkylene glycol, similarly obtains insoluble polymer.
The feature of third party's case of the Biodegradable particle in the present invention is that particle diameter is particle more than 5 μ m, and this particle is by the coating of polyalkylene glycol or derivatives thereof.
By the surface with wetting ability synthetic polymer coating Biodegradable particle, can give particle oilness.Herein, the wetting ability synthetic polymer in the present invention refers to swelling or water miscible synthetic polymer in water.Preferably being dissolved in body fluid due to indwelling, while being administered in body is discharged from, so preferably water-soluble synthetic polymer, as an example, can enumerate the polyalkylene glycol such as polyoxyethylene glycol, polypropylene glycol or derivatives thereof, polymethyl acrylic acid hydroxyl methyl esters, vinylformic acid, methacrylic acid, Polyvinylpyrolidone (PVP) etc., in the present invention, from the viewpoint of aggegation between particle, fixed moulding (cohesion) can not occur, use polyalkylene glycol or derivatives thereof.Particularly clinical from the viewpoint of being applied to, organism adaptability is high, most preferably polyoxyethylene glycol (hereinafter referred to as PEG).In addition, as a scheme of the coating in the present invention, can enumerate wetting ability synthetic polymer so that the state that the degree of particle surface generation surface modification is adsorbed, as long as give the degree of particle surface oilness by wetting ability synthetic polymer, be not particularly limited, the state that preferred particle is wrapped up by polyalkylene glycol or polyalkylene glycol moiety are attached to the state on particle.But in order more positively to give oilness, preferred hydrophilic synthetic polymer adheres to the more than 30% of surface-area of particle surface, more preferably more than 40%.As the method being layed onto on particle surface, can enumerate mechanical coating method, wet type coating method, spray-drying process, sugar-coat coating method, powder coated method etc.Wherein, preferably use wet type coating method and spray-drying process.Particularly in coating solution, stir particle, make the method for particle contact coating solution or particle is placed on strainer or sieve, from above to the wet type coating that flows down coating solution, particle contact coating solution is rinsed and easily adjust the adsorptive capacity of wetting ability synthetic polymer, so most preferably use.The degree of the molecular weight of above-mentioned polyalkylene glycol or derivatives thereof as long as adsorbing there is the degree of surface modification, be not particularly limited, if molecular weight is less than 1,000, owing to thering is the character for liquid under lower molecular weight normal temperature, particle surface is easily become aqueous, be difficult to process.In addition, in medical medical use, particularly injecting while giving in organism, if molecular weight is large, sometimes can not discharge from the renal glomerulus of kidney, is the polyalkylene glycol or derivatives thereof below 40,000 so preferably use molecular-weight average.Therefore, weight-average molecular weight is most preferably 1,000～40, in 000 scope.
As the method for wet type coating, can preferably use melting method, solvent cut method.The solvent of the solvent using in solvent cut method as long as the polymkeric substance using in coating being dissolved equably, also finally can being removed, is not particularly limited, and can enumerate the halogenide such as ketone, methylene dichloride such as the alcohols such as water, methyl alcohol, acetone etc.Cheap due to water, and safe, so particularly preferably make water.
As long as the concentration of PEG solution when wet type coating can be dissolved PEG equably, be not particularly limited, if concentration is too low, the surface property of particle does not improve, and sometimes in tubule, stops up, if too high, particle becomes high viscosity, sometimes application property variation.So, the most preferably scope of 1 % by weight～50 % by weight.
Make as described above, after the wet type coating of particle contact coating solution, to make particle dry, can obtain Biodegradable particle of the present invention.
Because wish that Biodegradable particle of the present invention is degraded and the degraded composition material that is absorbed or excretes in vivo after between given period, be the characteristic below 80% before flooding so preferably there is the residual weight of dipping after 28 days in the phosphate buffer normal saline (hereinafter to be referred as PBS) of 37 DEG C.That is, reduce because Biodegradable particle degraded causes its molecular weight, become in the PBS that is easily dissolved in 37 DEG C, so can evaluate biological degradability by These parameters.It should be noted that, said weight refers to the weight of the particle under drying regime herein.This residual weight is preferably below 70%, more preferably below 60%.
Weight measurement method to PBS dipping after 28 days is not particularly limited, for example, can adopt following method to measure.
(weight measurement method of PBS dipping after 28 days)
Accurate weighing 20mg (weight under drying regime) particle, put into sterilizing round bottom 10ml taper (spitz) pipe of Rong Yan equipment (strain) system, inject the PBS (NACALAI TESQUE (strain) system concentrated 10 times of pH7.4, Code.No.27575-31) of 10 times of 10ml pure water dilutions.It in the thermostatic bath " Laboster LC-110 " (Tabai Espec (strain) system) of setting 37 DEG C for, stir with " the Tube Rotertor TR-350 " of 100 revs/min (in (strain) well contain flourish hall system), is cultivated simultaneously.Solution after cultivating was carried out to a centrifugation every 7 days with 3000 revs/min, after separation of supernatant, be replaced by new PBS.
The particle flooding in PBS after 28 days is carried out to centrifugation with 3000 revs/min, remove supernatant liquor, then clean with the pure water of 10ml.Carry out centrifugation with 3000 revs/min again, remove pure water, carry out vacuum-drying to particle weight and reach stable, the weight of the particle that accurate weighing obtains.It should be noted that, refer to through the still state in 5% of a few hours changes in weight even if particle weight is stable herein.Weight (W before residual part by weight (W (%)) is flooded by PBS 0(g)), the weight (W of dipping after 28 days 1(g)), use W (%)=W 1/ W 0× 100 calculate.
It is the characteristic below 80% before dipping that Biodegradable particle of the present invention preferably has the weight-average molecular weight of flooding in the PBS of 37 DEG C after 28 days.And then preferably this weight-average molecular weight is below 70%, more preferably below 60%.Be the characteristic below 80% by there is the weight-average molecular weight of flooding after 28 days in the PBS of 37 DEG C, can carry out smoothly in vivo raw-material degraded, the stripping of particle, crushing, therefore after using unwanted particle in vivo shared volume reduce, the impact of human body is diminished.
The measuring method of molecular weight is not particularly limited, for example, can adopt following methods to measure.
(measuring method of weight-average molecular weight)
The 10mg particle of accurate weighing is dissolved in 2ml chloroform, uses gel permeation chromatography (hereinafter to be referred as GPC) to filter with strainer " Millex LG13 " (MILLIPORE SLLGH13NL).At (the eastern Cao TSK-gel-GMH of post for GPC hR-M) 2 pieces, 35 DEG C of column temperatures, moving phase measure filtrate under the condition of chloroform 1ml/min, sample injection rate 100 μ l, detect with differential refractive index meter (eastern Cao RI-8010 processed).Before starting, mensuration use eastern Cao's polystyrene standard to carry out the correction of post.
It should be noted that, molecular-weight average can be resolved with workstation ((strain) Shimadzu Seisakusho Ltd. system " Class-Vp ") by usage data, uses the typical curve being obtained by the molecular weight of polystyrene standard and the relation of post dissolution time to calculate.
In PBS, flood weight-average molecular weight after the 28 days ratio (M (%)) before with respect to PBS dipping and can use the weight-average molecular weight (M before PBS dipping 0), the weight-average molecular weight (M of dipping after 28 days 1), by M (%)=M 1/ M 0× 100 calculate.
It is the particle of the important document below 80% before dipping that Biodegradable particle of the present invention more preferably fully meets important document 80% below and the PBS dipping weight-average molecular weight 28 day after of the residual weight of PBS dipping after 28 days before dipping simultaneously.The method of adjusting biodegradation rate is not particularly limited, by adjusting the molecular weight of the Biodegradable polymer in multipolymer,, for example reduce the Biodegradable polymer molecular weight that uses multi-arm PEG derivatives chemical bonding, or the crystallinity of Biodegradable polymer in adjustment multipolymer, that is, for example, use PLGA as Biodegradable polymer, can more suitably adjust the biodegradation rate of particle.In addition, also preferably make the core part of Biodegradable particle there is inner dispersion type composite structure or incrusting type composite structure.By other different insoluble polymers of inner dispersion degradation speed in insoluble polymer or they are made to multilayered structure, for example in the insoluble polymer with PLA-PEG-PLA structure, inner dispersion has the insoluble polymer of PLGA-PEG-PLGA structure, can adjust the biodegradation rate of Biodegradable particle.
Purposes to Biodegradable particle of the present invention is not particularly limited, and is particularly preferred for using the medical medical use of conduit or pin, and then is preferably used as indwelling utensil (device) in vivo.
Said utensil refers to the device having to the treatment of disease or diagnosis, any function that prevention is relevant herein.To the size of installing, shape, starting material, structure etc., there is no particular limitation.For example can enumerate the drug delivery system of blood vessel embolism material or slow Slow release etc.
Biodegradable particle of the present invention can directly use, or is dispersed in suitable contrast medium or dispersion medium and uses while using.As contrast medium, preferably water dissolubility, can use known contrast medium, can be any in ionic, nonionic.Can enumerate particularly " Iopamilon " (Schering society system), " Hexabrix " (Rong Yan chemistry), " Omnipaque " (first pharmacy system), " Urografin " (Schering society system), " Iomeron " (defending material system) etc.Now, be injected into the position of regulation after particle and contrast medium can being mixed before use.If the aquosity of particle is high, a part for contrast medium and water together impregnation remain on inside particles, effectively show radiography, therefore more preferred.As dispersion medium, can enumerate dispersion agent (such as polyoxygenated sorbitan-fatty acid ester, carboxymethyl cellulose etc.), preservatives (such as para methyl paraben, propylparaben etc.), isotonic agent (such as sodium-chlor, N.F,USP MANNITOL, glucose etc.) are dissolved in to medium that distilled water for injection obtains or sesame oil, corn wet goods vegetables oil.When divided particles is used in conduit, be directed near the conduit desired site in body via front end, limit is by radioscopy control contrast locations, and limit gives particle by suitable artery towards tumour Nutrient arteries.
In above-mentioned Biodegradable particle, can add the sanitas that uses in common injection, stabilization agent, isotonic agent, solvable agent, dispersion agent, vehicle etc.
Biodegradable particle of the present invention can and be used with iodate seed of Papaver somniferum L. powder (Lipiodolultra fluide) as oil contrast media etc.In addition, can for example, by iodate seed of Papaver somniferum L. powder and anticarcinogen (zinostatin (smancs), neocarzinostatin (neocarzinostatin), ametycin (mitomycin C), Zorubicin (adriamycin), U 101440E (irinotecan hydrochloride), Fluracil (fluorouracil), Farmorubine Hydrochloride (epirubicin hydrochloride), cis-platinum (cisplatin), taxol (paclitaxel), Calciumlevofolinate (leucovorin calcium), vinealeucoblastine(VLB) (vinblastine), hexamethylmelamine (altretamine), bleomycin (bleomycin), doxorubicin hydrochloride (doxorubicin hydrochloride), Picibanil (picibanil), krestin (krestin), lentinan (lentinan), endoxan (cyclophosphamide), thio-tepa (thiotepa), Ftorafur (tegafur), Vinblastine sulphate (vinblastine sulfate), Pirarubicin (pirarubicin hydrochloride)) etc. and use.
Also can realize target of the present invention even if Biodegradable particle of the present invention does not comprise effective component, in order to give further effect, also preferably contain effective component.As effective component, as long as known medicative composition, be not particularly limited, can enumerate above-mentioned anticarcinogen, angiogenesis inhibitors, steroid hormone medicine, hepatic diseases medicine, gout therapertics, diabetes medicament, cardiovascular preparation, hyperlipidemia, bronchiectasis medicine, anti-allergy agent, digestion organs medication, anti-psychotropic, chemotherapeutic agent, antioxidant, peptide medicament, protein drug (such as Interferon, rabbit) etc.
Biodegradable particle of the present invention can be for various uses, can residual high security in vivo in view of its biological degradation, be best suited for medicine and medical field.In medicine medical use, be preferably used as medicine or cell etc. are transported to the carrier in organism.In addition, be suitable for most blocking tumour nutrient vessel, make tumour can not get the so-called embolotherapy of nutrient supply.
Embodiment
In the following embodiments, provide the experimental result of carrying out with regard to the conduit trafficability characteristic of particle, be described more specifically the present invention, scope of the present invention is not limited to following embodiment.Below, provide the measuring method in embodiment.
(median size, size-grade distribution)
Use Leeds & Northrup society (strain) particle size distribution device processed " Microtrac series ", in 25 DEG C of physiological saline, measure.Particle diameter uses the value calculating by volume averaging representing with " MV value ".
(compressive modulus of elasticity)
As compression testing machine, use MCT-W500 (strain) Shimadzu Seisakusho Ltd. system, under following condition, evaluate.
Testing laboratory's temperature: 25 DEG C
Testing laboratory's humidity: 50%
Top pressurization pressure head: flush type φ 500 μ m
Load speed: 4.462mN/sec
To the stress-strain curve that adopts aforesaid method to obtain, use following formula to obtain compressive modulus of elasticity.
Compressive modulus of elasticity (unit: MPa)=(δ 2-δ 1)/(ε 2-ε 1)
Herein, ε 1=0.0005, ε 2=0.0025, δ 1, δ 2 are stress under compressiones corresponding to ε 1, ε 2 of obtaining uniquely from stress-strain curve.
(modulus in tension of film)
As tensile testing machine, use (strain) Orientec RTM-100 type processed, under following condition, the film that adopts teeming practice formation is evaluated to modulus in tension.
Testing laboratory's temperature: 25 DEG C
Testing laboratory's humidity: 50%
Test film shape: rectangle (80mm × 7.5mm)
Test film thickness: 30 μ m ± 10 μ m
Chuck spacing: 20mm
Trial speed: 10mm/ minute
(weight measurement method of PBS dipping after 28 days)
Accurate weighing 20mg (weight of drying regime) particle, put into the sterilizing round bottom 10ml tapered tube of Rong Yan equipment (strain) system, inject the PBS (NACALAI TESQUE (strain) system concentrated 10 times of pH7.4, Code.No.27575-31) of 10 times of 10ml pure water dilutions.Put it in the thermostatic bath " Laboster LC-110 " (Tabai Espec (strain) system) that is set as 37 DEG C, stir with " the Tube Rotertor TR-350 " of 100 revs/min (containing flourish hall system in (strain) well), cultivate simultaneously.Every 7 days, the solution after cultivating is carried out to centrifugation with 3000 revs/min, after separation of supernatant, be replaced with new PBS.
Particle to PBS dipping after 28 days, carries out, after centrifugation, removing supernatant liquor with 3000 revs/min, and then clean with the pure water of 10ml, then carry out centrifugation with 3000 revs/min, remove after pure water, vacuum-drying to particle weight reaches stable, the weight of the particle that accurate weighing obtains.Weight (W before residual part by weight (W) can be flooded by PBS 0(g)), the weight (W of dipping after 28 days 1(g)) use W=W 1/ W 0× 100 calculate.
(measuring method of weight-average molecular weight)
The 10mg particle of accurate weighing is dissolved in 2ml chloroform, uses gel permeation chromatography (hereinafter to be referred as GPC) to filter with strainer " Millex LG13 " (MILLIPORE SLLGH13NL).At (the eastern Cao TSK-gel-GMH of post for GPC hR-M) 2 pieces, 35 DEG C of column temperatures, moving phase analyze this filtrate under the condition of chloroform 1ml/min, sample injection rate 100 μ l, measure with differential refractive index meter (eastern Cao RI-8010 processed).Before starting, mensuration use eastern Cao's polystyrene standard coupled columns to proofread and correct.
It should be noted that, molecular-weight average usage data is resolved with workstation ((strain) Shimadzu Seisakusho Ltd. system " Class-Vp "), utilizes the typical curve of being obtained by the molecular weight of polystyrene standard and the relation of post dissolution time to calculate.
(polyoxyethylene glycol containing ratio method of calculation)
Make 0.1g polymer dissolution in the deuterochloroform of 1mL, by 270MHz superconduction FT-NMR EX-270 (JOEL society system) mensuration 1h-NMR.
The relative integral value of the signal of the chemical shift 3.4-3.7ppm of 4 hydrogen atoms of the ethylidene from polyoxyethylene glycol is represented with A, relative integral value from the signal of the chemical shift 1.4-1.6ppm of 3 hydrogen atoms of the methyl of lactic acid units represents with B, while expression with C from the relative integral value of the signal of the chemical shift 4.7-4.9ppm of 2 hydrogen atoms of the methylene radical of oxyacetic acid unit, use the molecular weight 44,72,58 of each repeating unit, represent the content of polyoxyethylene glycol with following formula.
Content (%)=100 × (44 × A/4)/((44 × A/4)+(72 × B/3)+(58 × C/2))
(conduit trafficability characteristic)
The particle dispersion obtaining in each embodiment, comparative example is injected in conduit from syringe, is zero according to can inject without resistance time, produces when resistance cannot inject and be × evaluate.But, for embodiment 4～6, comparative example 2～5, be zero when can injecting without resistance and keep spherical by Postductal particle, can inject without resistance, but while not keeping spherical by Postductal particle, be △, produce when resistance cannot inject and be × evaluate.As conduit, unless stated otherwise, (the long 155cm of conduit, leading section internal diameter 380 μ are m) to use the rider FasTRACKER-10 Infusion Catheter of Boston Scient Scimed Inc. (BOSTON SCIENTIFIC).
< Production Example 1>
In nitrogen gas stream, in flask, mix 4.96g L-rac-Lactide (PURACBIOCHEM society system), PEG (Japanese oil prodution industry SUNBRIGHT DKH-20T processed) after 1.66g glycollide (BoehringerIngelheim society system) and 2.88g dehydration, at 150 DEG C, make it dissolve after mixing, add 460 μ L and be dissolved with two stannous octoates (with the pure pharmaceutical worker of light industry system), and the toluene solution that its concentration is 0.1mol/L, make its reaction, the insoluble polymer that the water-soluble polymers weight ratio that obtains having PLGA-PEG-PLGA structure is 30.3%.This insoluble polymer is dissolved in chloroform, splashes in greatly excessive ether/acetone mixed solution, obtain white precipitate.The weight-average molecular weight of utilizing above-mentioned GPC method to record is 22,000.
By the refining polymer dissolution obtaining, in methylene dichloride, concentration is 30 % by weight.This solution is injected in the cultivation ware of internal diameter 85mm, at 20 DEG C, places 1 round the clock, make methylene dichloride evaporation, carry out membranization, obtain the film of thickness 20 μ m.When it is impregnated in pure water at normal temperatures, within approximately 3 hours, water ratio reaches stable.While carrying out the tension test under saturated moisture state, the modulus in tension of film is 57MPa.
< Production Example 2>
In nitrogen gas stream, in flask, mix the PEG (Japanese oil prodution industry SUNBRIGHT MEH-20T processed) after 1.92g L-rac-Lactide (PURACBIOCHEM society system), 0.96g glycollide (BoehringerIngelheim society system) and 2.88g dehydration, adopt the method identical with Production Example 1, make its dissolving mix and react, the insoluble polymer that the water-soluble polymers weight ratio that obtains having PLGA-PEG structure is 50.0%.By this insoluble polymer, adopt the method identical with Production Example 1 to obtain white precipitate.The weight-average molecular weight of utilizing above-mentioned GPC method to record is 14,000.
The refining polymkeric substance that use obtains, similarly carries out membranization with Production Example 1, obtains the film of thickness 20 μ m.When it is immersed in pure water at normal temperatures, within approximately 3 hours, weight reaches stable.While carrying out the tension test under moisture state, the modulus in tension of film is 2.1MPa.
[table 1]
< embodiment 1>
The insoluble polymer obtaining in Production Example 1 is mixed by the weight ratio of 70: 30 with the water-insoluble copolymer obtaining in Production Example 2, be dissolved in methylene dichloride.Be added dropwise in 1 % by weight polyvinyl alcohol (Aldrich society system, the Cat.No.360627) aqueous solution, carry out O/W fluid drying, obtain spherical particle dispersion liquid.
Then, with nylon sieve (cut-off (cutoff) particle diameter: 65 μ m, 185 μ m, 260 μ m, 360 μ m, 540 μ m) carry out after wet classification, carry out vacuum-drying, obtain without aggegation, fixed dry spherical particle.The each 40mg of particle reclaiming respectively on the sieve of 4 kinds of sizes except 540 μ m from above-mentioned cut-off particle diameter is distributed in 1mL PBS, measure median size and size-grade distribution, median size and the size-grade distribution of the particle being reclaimed by the sieve of 4 kinds of sizes are respectively 125 ± 60 μ m, 220 ± 40 μ m, 310 ± 50 μ m, 450 ± 90 μ m.
When above-mentioned particle dispersion is carried out to the evaluation of conduit trafficability characteristic, median size is that the particle of 125 μ m and 220 μ m can inject without resistance, although how many particles that median size is 310 μ m, 450 μ m shows some resistances, also can pass through conduit.Then, conduit is cut along long axis direction, in visual inspection conduit time, do not observe spherical particle.
Using the compression testing machine MCT-W500 processed of (strain) Shimadzu Seisakusho Ltd. to measure median size is the compressive modulus of elasticity of the particle of 310 μ m, and result is 1.4 ± 0.3MPa.
Evaluate this particle and in PBS, flood the degradation property after 28 days, result is compared with before dipping, and the ratio of residual weight is 30%, and the ratio of weight-average molecular weight is 70%.
< embodiment 2>
The insoluble polymer obtaining in the insoluble polymer obtaining in Production Example 1 and Production Example 2 is mixed by the weight ratio of 50: 50, in addition, adopt the method identical with embodiment 1 to obtain spherical particle dispersion liquid.
Then, adopt after the method wet classification identical with embodiment 1, carry out vacuum-drying, aggegation, fixed dry spherical particle are not occurred.Measure median size and the size-grade distribution of this particle, the result of each particle that result is reclaimed by the sieve of 4 kinds of sizes is respectively 125 ± 60 μ m, 220 ± 40 μ m, 310 ± 50 μ m, 450 ± 90 μ m.
Above-mentioned particle dispersion is injected into the conduit identical with embodiment 1 from syringe, and the particle of the whole median sizes of result all can pass through conduit without resistance.Then, conduit is cut along long axis direction, in visual inspection conduit, do not observe spherical particle.
Measuring median size is the compressive modulus of elasticity of the particle of 310 μ m, and result is 2.0 ± 0.5MPa.
Evaluate this particle and in PBS, flood the degradation property after 28 days, result is compared with before dipping, and the ratio of residual weight is 30%, and the ratio of weight-average molecular weight is 70%.
< embodiment 3>
Adopt the method identical with embodiment 1 to obtain spherical particle dispersion liquid.Then, adopt after the method wet classification identical with embodiment 1, rinse with PEG (with the pure pharmaceutical worker's industry of light molecular-weight average 4, the 000 processed) aqueous solution of about 200mL 5 % by weight, carry out vacuum-drying, aggegation or fixed dry spherical particle are not occurred.Measure median size and the size-grade distribution of this particle, the result of the particle being reclaimed by the sieve of 4 kinds of sizes is respectively 125 ± 60 μ m, 220 ± 40 μ m, 310 ± 50 μ m, 450 ± 90 μ m.
Above-mentioned particle dispersion is injected into the conduit identical with embodiment 1 from syringe, result median size is that the particle of 125 μ m and 220 μ m can inject without resistance, show a little resistance although median size is the particle of 310 μ m, 450 μ m, also can pass through conduit.Then, conduit is cut along long axis direction, in visual inspection conduit, do not observe spherical particle.
Measuring median size is the compressive modulus of elasticity of the particle of 310 μ m, and result is 1.3 ± 0.3MPa.
Evaluate this particle and in PBS, flood the degradation property after 28 days, result is compared with before dipping, and the ratio of residual weight is 30%, and the ratio of weight-average molecular weight is 70%.
As mentioned above, there is spherical particle that the polymkeric substance of insoluble polymer and insoluble polymer forms can be less than by internal diameter the conduit of particle diameter by fusion.
< comparative example 1>
Only use the insoluble polymer obtaining in Production Example 1, in addition, adopt the method identical with embodiment 1 to obtain spherical particle dispersion liquid.
Then, adopt after the method wet classification identical with embodiment 1, carry out vacuum-drying, aggegation, fixed dry spherical particle are not occurred.Measure median size and the size-grade distribution of this particle, the result of the particle being reclaimed by the sieve of 4 kinds of sizes is respectively 125 ± 60 μ m, 220 ± 40 μ m, 310 ± 50 μ m, 450 ± 90 μ m.
Above-mentioned particle dispersion is injected into the conduit identical with embodiment 1 from syringe, and result median size is that the particle of 125 μ m and 220 μ m can inject without resistance, and median size is that the particle of 310 μ m, 450 μ m can not pass through conduit.Then, conduit is cut along long axis direction, in visual inspection conduit, result is observed spherical particle.
Measuring median size is the compressive modulus of elasticity of the particle of 310 μ m, and result is 14.4 ± 2.9MPa.
Evaluate this particle and in PBS, flood the degradation property after 28 days, result is compared with before dipping, and the ratio of residual weight is 28%, and the ratio of weight-average molecular weight is 63%.
[table 2]
< Production Example 3>
In nitrogen gas stream, in flask, mix the PEG (Japanese oil prodution industry SUNBRIGHT DKH-20T processed) after 4.96g L-rac-Lactide (PURACBIOCHEM society system), 1.66g glycollide (BoehringerIngelheim society system) and 2.88g dehydration, at 150 DEG C, make it dissolve after mixing, adding 460 μ L is dissolved with in the toluene solution that two stannous octoates (with the pure pharmaceutical worker of light industry system) and its concentration are 0.1mol/L, make its reaction, obtain having the multipolymer of PLGA-PEG-PLGA structure.This multipolymer is dissolved in chloroform, splashes in greatly excessive ether/acetone mixed solution, obtain white precipitate.The weight-average molecular weight of utilizing above-mentioned GPC method to record is 58,000.
< Production Example 4>
In nitrogen gas stream, in flask, mix the PEG (Japanese oil prodution industry SUNBRIGHT MEH-20T processed) after 1.42g L-rac-Lactide (PURACBIOCHEM society system), 1.44g glycollide (BoehringerIngelheim society system) and 2.88g dehydration, at 150 DEG C, make it dissolve after mixing, add 460 μ L and be dissolved with the toluene solution that two stannous octoates (with the pure pharmaceutical worker of light industry system) and its concentration are 0.1mol/L, make its reaction, obtain having the multipolymer of PLGA-PEG-PLGA structure.This multipolymer is dissolved in chloroform, splashes in greatly excessive ether/acetone mixed solution, obtain white precipitate.The weight-average molecular weight of utilizing above-mentioned GPC method to record is 42,000.
< embodiment 4>
Refining multipolymer shown in Production Example 3,4 is dissolved in to methylene dichloride by the weight ratio of 7: 3, by O/W intra-liquid desiccation method, obtains spheroidal particle.By this spheroidal particle vacuum-drying, then use nylon screen classification.This classification particle is immersed in physiological saline, obtains the dispersion liquid that contains spheroidal particle.While measuring size-grade distribution, volume average particle size approximately 450 μ m, distribution range is median size ± 90 μ m, maximum particle diameter is about 540 μ m.Mensuration particle 1h-NMR, result polyoxyethylene glycol is 0.61 with respect to the weight content ratio of poly-(lactide/glycolides) multipolymer.
Study the conduit trafficability characteristic of this particle, result can without any problem inject conduit, being shaped as of the particle by leading section is spherical.Although 30% distortion occurs the particle that maximum diameter is 540 μ m in conduit, the shape of the particle passing through still, for spherical, reverts to the diameter that is greater than catheter diameter.It should be noted that, in phosphate buffer normal saline (pH7.4), add above-mentioned spheroidal particle, at 37 DEG C, after 28 days, obtain the ratio of residual weight compared with weight before treatment, result is 30%.
< embodiment 5>
Refining multipolymer shown in Production Example 3,4 is dissolved in methylene dichloride by the weight ratio of 55: 45, in addition, adopts the method identical with embodiment 4 to obtain the dispersion liquid that contains spheroidal particle.Measure size-grade distribution, result volume average particle size is about 450 μ m, and distribution range is median size ± 90 μ m, and maximum particle diameter is approximately 540 μ m.Mensuration particle 1h-NMR, result polyoxyethylene glycol is 0.69 with respect to the weight content ratio of poly-(lactide/glycolides) multipolymer.
Research conduit trafficability characteristic, result can without any problem inject, being shaped as of the particle by leading section is spherical.Although 30% distortion occurs the particle that maximum diameter is 540 μ m in conduit, the shape of the particle passing through still, for spherical, reverts to the diameter that is greater than catheter diameter.It should be noted that, in phosphate buffer normal saline (pH7.4), add above-mentioned spheroidal particle, at 37 DEG C, after 28 days, obtain the ratio of residual weight compared with weight before treatment, result is 35%.
< embodiment 6>
Refining multipolymer shown in Production Example 3,4 is dissolved in methylene dichloride by the weight ratio of 65: 35, in addition, adopts the method identical with embodiment 4 to obtain the dispersion liquid containing spheroidal particle.Measure size-grade distribution, result volume average particle size is about 450 μ m, and distribution range is median size ± 90 μ m, and maximum particle diameter is about 540 μ m.Mensuration particle 1h-NMR, result polyoxyethylene glycol is 0.63 with respect to the weight content ratio of poly-(lactide/glycolides) multipolymer.
Research conduit trafficability characteristic, result can without any problem inject, being shaped as of the particle by leading section is spherical.Although 30% distortion occurs the particle that maximum diameter is 540 μ m in conduit, the shape of the particle passing through still, for spherical, reverts to the diameter that is greater than catheter diameter.It should be noted that, in phosphate buffer normal saline (pH7.4), add above-mentioned spheroidal particle, at 37 DEG C, after 28 days, obtain the ratio of residual weight compared with weight before treatment, result is 30%.
< is Production Example 1> relatively
In nitrogen gas stream, in flask, mix 40.3g L-rac-Lactide (PURACBIOCHEM society system), 8.1mg bis-stannous octoates (with the pure pharmaceutical worker's industry of light (strain) system), it is reacted at 140 DEG C, gathered (L-rac-Lactide).The polymer dissolution obtaining, in chloroform, is splashed in greatly excessive methyl alcohol, obtain white depositions.Utilizing the weight-average molecular weight that GPC method records is approximately 70,000.
< comparative example 2>
To compare the polymer dissolution obtaining in Production Example 1 in methylene dichloride, in addition, adopt the method identical with embodiment 4 to obtain the dispersion liquid containing spheroidal particle.Measure size-grade distribution, result volume average particle size is about 450 μ m, and distribution range is median size ± 90 μ m, and maximum particle diameter is about 540 μ m.Mensuration particle 1h-NMR, result polyoxyethylene glycol is 0.00 with respect to the weight content ratio of polylactide.Study the conduit trafficability characteristic of the spheroidal particle dispersion liquid of this poly-(L-rac-Lactide), result starts after conductive pipe is injected to produce at once strong resistance, cannot inject simultaneously.Although some particle is by leading section, most particles all fail to pass through microtubular.In addition, (the about Isosorbide-5-Nitrae 00mm of total length, leading section internal diameter approximately 680 μ are m) time, inject after starting and produce at once strong resistance, cannot inject simultaneously to inject the rider MASS TRANSIT of CORDIS company (Cordis Corporation).Although some particle is by leading section, most particles all fail to pass through microtubular.It should be noted that, in phosphate buffer normal saline (pH7.4), add above-mentioned spheroidal particle, at 37 DEG C, after 28 days, obtain the ratio of residual weight compared with weight before treatment, result is 98%.
< is Production Example 2> relatively
In nitrogen gas stream, the molecular-weight average 8 after melting mixing 40.3g L-rac-Lactide (PURACBIOCHEM society system) and 8.3g dehydration at 140 DEG C in flask, after 000 polyoxyethylene glycol (Japanese grease DKH-80H processed), add 8.1mg bis-stannous octoates (with the pure pharmaceutical worker's industry of light (strain) system), it is reacted at 180 DEG C, obtain A-B-A type multipolymer (PLA-PEG-PLA).The multipolymer obtaining is dissolved in chloroform, splashes in greatly excessive methyl alcohol, obtain white depositions.Utilizing the weight-average molecular weight that GPC method records is approximately 47,000.
< comparative example 3>
Above-mentioned refining multipolymer is dissolved in methylene dichloride, in addition, adopts the method identical with embodiment 4 to obtain the dispersion liquid containing spheroidal particle.Measure size-grade distribution, result volume average particle size is about 450 μ m, and distribution range is median size ± 90 μ m, and maximum particle diameter is about 540 μ m.Mensuration particle 1h-NMR, result polyoxyethylene glycol is 0.11 with respect to the weight content ratio of polylactide.Research conduit trafficability characteristic, result starts after conductive pipe is injected to produce at once strong resistance, cannot inject simultaneously.Although some particle is by leading section, most particles fail to pass through microtubular.In addition, (the about Isosorbide-5-Nitrae 00mm of total length, leading section internal diameter approximately 680 μ are m) time, inject after starting and produce at once strong resistance, cannot inject simultaneously to inject the rider MASS TRANSIT of CORDIS company (Cordis Corporation).Although some particle is by leading section, most particles cannot pass through microtubular.It should be noted that, in phosphate buffer normal saline (pH7.4), add above-mentioned spheroidal particle, at 37 DEG C, after 28 days, obtain the ratio of residual weight compared with weight before treatment, result is 98%.
< comparative example 4>
Refining multipolymer shown in Production Example 3,4 is dissolved in methylene dichloride by the weight ratio of 3: 7, in addition, adopts the method identical with embodiment 4 to obtain the dispersion liquid containing spheroidal particle.Measure size-grade distribution, result volume average particle size is about 450 μ m, and distribution range is median size ± 90 μ m, and maximum particle diameter is about 540 μ m.Mensuration particle 1h-NMR, result polyoxyethylene glycol is 0.83 with respect to the weight content ratio of poly-(lactide/glycolides) multipolymer.
Research conduit trafficability characteristic, result can without any problem inject conduit.But, by the particle deformation fracture of conduit, do not keep spherical.It should be noted that, in phosphate buffer normal saline (pH7.4), add above-mentioned spheroidal particle, at 37 DEG C, after 28 days, obtain the ratio of residual weight compared with weight before treatment, result is 40%.
< comparative example 5>
Refining multipolymer shown in Production Example 4 is dissolved in methylene dichloride, by O/W intra-liquid desiccation method, modulation spheroidal particle, spherical but particle does not become.Use this particle, adopt the method identical with embodiment 4 to obtain containing dispersion of particles liquid.Measure size-grade distribution, result volume average particle size is about 450 μ m, and distribution range is median size ± 90 μ m, and maximum particle diameter is about 540 μ m.Mensuration particle 1h-NMR, result polyoxyethylene glycol is 1.04 with respect to the weight content ratio of poly-(lactide/glycolides) multipolymer.
Research conduit trafficability characteristic, result can without any problem inject conduit.But, by the particle deformation fracture of conduit, do not keep spherical.It should be noted that, in phosphate buffer normal saline (pH7.4), add above-mentioned spheroidal particle, at 37 DEG C, after 28 days, obtain the ratio of residual weight compared with weight before treatment, result is 40%.
[table 3]
[table 4]
Conduit trafficability characteristic zero: can inject without resistance, by after particle be spherical
△: can inject without resistance, but by after particle be not spherical
×: fail to inject
< Production Example 5>
In nitrogen gas stream, in flask, mix the PEG (Japanese oil prodution industry SUNBRIGHT DKH-20T processed) after 6.6g L-rac-Lactide (PURACBIOCHEM society system) and 2.9g dehydration, at 150 DEG C, make it dissolve after mixing, add 460 μ L and be dissolved with the toluene solution that two stannous octoates (with the pure pharmaceutical worker of light industry system) and its concentration are 0.1mol/L, make its reaction, obtain having the multipolymer of PLA-PEG-PLA structure.This multipolymer is dissolved in chloroform, splashes in greatly excessive ether/acetone mixed solution, obtain white precipitate.The weight-average molecular weight of utilizing above-mentioned GPC method to record is 15,000.
< embodiment 7>
The refining multipolymer obtaining in 1.0g Production Example 5 is dissolved in 30mL methylene dichloride, splashes in 1 % by weight polyvinyl alcohol (Aldrich society system, the Cat.No.360627) aqueous solution, carry out O/W fluid drying, obtain spherical particle dispersion liquid.The supernatant of this dispersion liquid of decant, is replaced by the PEG (with the pure pharmaceutical worker's industry of light molecular-weight average 600 processed) of 10 % by weight, stirs 30 minutes.Then, sieve and carry out, after wet classification, carrying out vacuum-drying with nylon, obtain dry spherical particle.Particle surface is gel.
The size-grade distribution of measuring this particle of 40mg, result is as shown in table 6.The conduit trafficability characteristic of evaluating as stated above this particle dispersion, result can be injected without resistance.Then, conduit is cut along long axis direction, visual inspection inside, does not observe spherical particle.
Evaluating this particle, in PBS, to flood the result of the degradation property after 28 days as shown in table 6.
In addition, with after nylon sieve wet classification, carry out vacuum-drying, the particle obtaining is immersed in physiological saline, obtain particle dispersion.Then, with Sodital anesthesia 2 10 weeks age rat the remaining needle of thigh intravenously insertion 24G after, inject this spherical particle dispersion liquid by conduit.After 28 days, lung is carried out to outward appearance observation, and make tissue slice, inject after spherical particle dispersion liquid, tissue slice is observed, all observe lung infraction for 2 as a result, and then can confirm particle degraded.
< embodiment 8>
The dispersion liquid of the spherical particle obtaining through O/W fluid drying in embodiment 7 is sieved to wet classification with nylon, then use PEG (with the pure pharmaceutical worker's industry of the light molecular-weight average 600 processed) aqueous solution of about 200mL 10 % by weight to rinse, carry out vacuum-drying, obtain dry spherical particle.Particle surface is gel.
The size-grade distribution of measuring this particle, result is as shown in table 6.The conduit trafficability characteristic of evaluating according to the method described above this particle dispersion, result can be injected without resistance.Then, conduit is cut along long axis direction, visual inspection inside, does not observe spherical particle.
In addition, evaluate this particle and in PBS, flood the degradation property after 28 days, the results are shown in table 6.
< embodiment 9>
The dispersion liquid of the spherical particle obtaining by O/W fluid drying in embodiment 7 is sieved after wet classification with nylon, with the PEG of about 200mL 1 % by weight (with the pure pharmaceutical worker's industry of light molecular-weight average 1 processed, 000) aqueous solution rinses, and carries out vacuum-drying, obtains dry spherical particle.Particle surface is dry and smooth.
The size-grade distribution of measuring this particle, result is as shown in table 6.This particle dispersion is injected in conduit, evaluate its trafficability characteristic, result can be injected without resistance.Then, conduit is cut along long axis direction, visual inspection inside, does not observe spherical particle.
In addition, evaluate this particle and in PBS, flood the degradation property after 28 days, result is as shown in table 6.
< embodiment 10>
The dispersion liquid of the spherical particle obtaining by O/W fluid drying in embodiment 7 is sieved after wet classification with nylon, with the PEG of about 200mL 1 % by weight (with the pure pharmaceutical worker's industry of light molecular-weight average 1 processed, 000) aqueous solution rinses, and carries out vacuum-drying and obtains dry spherical particle.Particle surface is dry and smooth.
The size-grade distribution of measuring this particle, result is as shown in table 6.The conduit trafficability characteristic of evaluating according to the method described above this particle dispersion, result can be injected without resistance.Then, conduit is cut along long axis direction, visual inspection inside, does not observe spherical particle.
In addition, evaluate this particle and in PBS, flood the degradation property after 28 days, the results are shown in table 6.
< embodiment 11>
The dispersion liquid of the spherical particle obtaining by O/W fluid drying in embodiment 7 is sieved after wet classification with nylon, with the PEG of about 200mL 3 % by weight (with the pure pharmaceutical worker's industry of light molecular-weight average 1 processed, 000) aqueous solution rinses, and carries out vacuum-drying, obtains dry spherical particle.Particle surface is dry and smooth.
The size-grade distribution of measuring this particle, result is as shown in table 6.The conduit trafficability characteristic of evaluating according to the method described above this particle dispersion, result can be injected without resistance.Then, conduit is cut along long axis direction, visual inspection inside, does not observe spherical particle.
In addition, evaluate this particle and in PBS, flood the degradation property after 28 days, the results are shown in table 6.
< embodiment 12>
The dispersion liquid of the spherical particle obtaining by O/W fluid drying in embodiment 7 is sieved after wet classification with nylon, with the PEG of about 200mL 3 % by weight (with the pure pharmaceutical worker's industry of light molecular-weight average 1 processed, 000) aqueous solution rinses, and carries out vacuum-drying, obtains dry spherical particle.Particle surface is dry and smooth.
The size-grade distribution of measuring this particle, result is as shown in table 6.The conduit trafficability characteristic of evaluating according to the method described above this particle dispersion, result can be injected without resistance.Then, conduit is cut along long axis direction, visual inspection inside, does not observe spherical particle.
In addition, evaluate this particle and in PBS, flood the degradation property after 28 days, the results are shown in table 6.
< embodiment 13>
The dispersion liquid of the spherical particle obtaining by O/W fluid drying in embodiment 7 is sieved after wet classification with nylon, with the PEG of about 200mL 20 % by weight (with the pure pharmaceutical worker's industry of light molecular-weight average 1 processed, 000) aqueous solution rinses, and carries out vacuum-drying, obtains dry spherical particle.Particle surface is dry and smooth.
The size-grade distribution of measuring this particle, result is as shown in table 6.The conduit trafficability characteristic of evaluating according to the method described above this particle dispersion, result can be injected without resistance.Then, conduit is cut along long axis direction, visual inspection inside, does not observe spherical particle.
In addition, evaluate this particle and in PBS, flood the degradation property after 28 days, the results are shown in table 6.
< embodiment 14>
The dispersion liquid of the spherical particle obtaining by O/W fluid drying in embodiment 7 is sieved after wet classification with nylon, with the PEG of about 200mL 5 % by weight (with the pure pharmaceutical worker's industry of light molecular-weight average 4 processed, 000) aqueous solution rinses, and carries out vacuum-drying, obtains dry spherical particle.Particle surface is dry and smooth.
The size-grade distribution of measuring this particle, result is as shown in table 6.The conduit trafficability characteristic of evaluating according to the method described above this particle dispersion, result can be injected without resistance.Then, conduit is cut along long axis direction, visual inspection inside, does not observe spherical particle.
In addition, evaluate this particle and in PBS, flood the degradation property after 28 days, the results are shown in table 6.
< Production Example 6>
In nitrogen gas stream, in flask, mix the PEG (Japanese oil prodution industry SUNBRIGHT DKH-20T processed) after 5.0g L-rac-Lactide (PURACBIOCHEM society system), 1.7g glycollide (BoehringerIngelheim society system) and 2.9g dehydration, at 150 DEG C, make it dissolve after mixing, add 490 μ L and be dissolved with the toluene solution that two stannous octoates (with the pure pharmaceutical worker of light industry system) and its concentration are 0.1mol/L, make its reaction, obtain having the multipolymer of PLGA-PEG-PLGA structure.This multipolymer is dissolved in chloroform, splashes in greatly excessive ether/acetone mixed solution, obtain white precipitate.Utilizing the weight-average molecular weight that GPC method records is 22,000.
< embodiment 15>
Similarly to Example 7 above-mentioned 0.5mg refining multipolymer is dissolved in 19mL methylene dichloride, splashes in 1 % by weight polyvinyl alcohol water solution, carry out O/W fluid drying, obtain spherical particle dispersion liquid.This dispersion liquid, with after nylon sieve wet classification, with PEG (with the pure pharmaceutical worker's industry of light molecular-weight average 1, the 000 processed) aqueous solution flushing of about 200mL 5 % by weight, is carried out to vacuum-drying, obtain the dry spherical particle that shape is consistent.Particle surface is dry and smooth.
The size-grade distribution of measuring this particle, result is as shown in table 6.The conduit trafficability characteristic of evaluating according to the method described above this particle dispersion, result can be injected without resistance.Then, conduit is cut along long axis direction, visual inspection inside, does not observe spherical particle.
Evaluate this particle and in PBS, flood the degradation property after 28 days, the results are shown in table 6.
In addition, this particle, with after nylon sieve wet classification, is carried out to vacuum-drying, the particle obtaining is immersed in physiological saline, obtain particle dispersion.Then, with Sodital anesthesia 2 10 weeks age rat the remaining needle of thigh intravenously insertion 24G after, inject this spherical particle dispersion liquid by conduit.After 28 days, lung is carried out to outward appearance observation, and make tissue slice, after injection spherical particle dispersion liquid, tissue slice is observed, all observe lung infraction for 2 as a result, and then can confirm particle degraded.
< embodiment 16>
The dispersion liquid of the spherical particle obtaining by O/W fluid drying in embodiment 15 is sieved after wet classification with nylon, with the PEG of about 200mL 5 % by weight (with the pure pharmaceutical worker's industry of light molecular-weight average 1 processed, 000) aqueous solution rinses, carry out vacuum-drying, obtain the dry spherical particle that shape is consistent.Particle surface is dry and smooth.
The size-grade distribution of measuring this particle, result is as shown in table 6.The conduit trafficability characteristic of evaluating according to the method described above this particle dispersion, result can be injected without resistance.Then, conduit is cut along long axis direction, visual inspection inside, does not observe spherical particle.
In addition, evaluate this particle and in PBS, flood the degradation property after 28 days, the results are shown in table 6.
Hence one can see that, and particle surface, by the particle of PEG coating, aggegation or the moulding of fixed ground between particle can not occurred, and can not produce resistance, stops up and pass through during by microtubular.
< comparative example 6>
The dispersion liquid of the spherical particle obtaining by O/W fluid drying in embodiment 7, with after nylon sieve wet classification, is carried out to vacuum-drying and obtains dry spherical particle.
The size-grade distribution of measuring this particle, result is as shown in table 6.Evaluate according to the method described above the conduit trafficability characteristic of this particle dispersion, after injection starts, at the connector part of duct entry, spherical particle aggegation, produces strong resistance, cannot inject simultaneously.
< comparative example 7>
The dispersion liquid of the spherical particle obtaining by O/W fluid drying in embodiment 7, with after nylon sieve wet classification, is carried out to vacuum-drying and obtains dry spherical particle.
For this particle, in its dispersion liquid, dissolve/stir 10mg PEG (with the pure pharmaceutical worker's industry of light molecular-weight average 1000 processed), measure size-grade distribution, result is as shown in table 6.Evaluate according to the method described above the conduit trafficability characteristic of this particle dispersion, inject the connector part spherical particle aggegation at duct entry after starting, produce strong resistance, can not inject simultaneously.
< comparative example 8>
The dispersion liquid of the spherical particle obtaining by O/W fluid drying in embodiment 8, with after nylon sieve wet classification, is carried out to vacuum-drying, obtain dry spherical particle.
The size-grade distribution of measuring this particle, result is as shown in table 6.Evaluate according to the method described above the conduit trafficability characteristic of this particle dispersion, after injection starts, in the connector part spherical particle aggegation of duct entry, produce strong resistance, can not inject simultaneously.
< comparative example 9>
The dispersion liquid of the spherical particle obtaining by O/W fluid drying in embodiment 9, with after nylon sieve wet classification, is carried out to vacuum-drying, obtain dry spherical particle.
The size-grade distribution of measuring this particle, result is as shown in table 6.Evaluate according to the method described above the conduit trafficability characteristic of this particle dispersion, after injection starts, in the connector part spherical particle aggegation of duct entry, produce strong resistance, can not inject simultaneously.
< comparative example 10>
The dispersion liquid of the spherical particle obtaining by O/W fluid drying in embodiment 15, with after nylon sieve wet classification, is carried out to vacuum-drying, obtain being mixed with the particle drying particulate of the material of aggegation or fixed formation each other.
The particle that particle in this drying particulate is not occurred each other to for aggegation, fixed particle diameter approximately 300 μ m carries out particle size distribution, and result is as shown in table 6.Evaluate according to the method described above the conduit trafficability characteristic of this particle dispersion, after injection starts, in the connector part spherical particle aggegation of duct entry, produce strong resistance, can not inject simultaneously.

Claims (15)

1. a Biodegradable particle, it is characterized in that, the particle diameter of described Biodegradable particle is more than 5 μ m, it is 1 that the core part of described particle contains weight-average molecular weight, 000～100,000 water-insoluble polyalkylene glycols multipolymer, described water-insoluble polyalkylene glycols multipolymer is to obtain by polyalkylene glycol or derivatives thereof and the Biodegradable polymer chemical bonding that contains alpha hydroxy acid unit; And, have polyalkylene glycol or derivatives thereof in surface attachment or the absorption of described core part.
2. Biodegradable particle as claimed in claim 1, is characterized in that, is more than 1,000, below 40,000 in the weight-average molecular weight of the surface attachment of described core part or the described polyalkylene glycol of absorption.
3. Biodegradable particle as claimed in claim 1 or 2, is characterized in that, is polyoxyethylene glycol in the surface attachment of described core part or the described polyalkylene glycol of absorption.
4. Biodegradable particle as claimed in claim 1, is characterized in that, the particle diameter of described particle is 5～2000 μ m.
5. Biodegradable particle as claimed in claim 1, is characterized in that, the size-grade distribution of described particle median size ± 60% in.
6. the Biodegradable particle as described in claim 4 or 5, is characterized in that, described particle is spherical.
7. Biodegradable particle as claimed in claim 1, it is characterized in that, described Biodegradable particle has base material, described base material contains water-soluble polymers and Biodegradable polymer, and described water-soluble polymers is 0.60～0.70 with respect to the content ratio of described Biodegradable polymer.
8. Biodegradable particle as claimed in claim 1, is characterized in that, described Biodegradable particle has degradation property in the phosphate buffer normal saline of 37 DEG C.
9. Biodegradable particle as claimed in claim 1, it is characterized in that, the median size of described Biodegradable particle is more than 100 μ m, and the Postductal particle diameter more than 60%, below 85% that 'go'gage is its particle diameter under saturated aqueous state is greater than the bore of described conduit.
10. Biodegradable particle as claimed in claim 1, is characterized in that, the compressive modulus of elasticity of the particle under saturated aqueous state is below 10MPa.
11. Biodegradable particles as claimed in claim 1, is characterized in that, the weight-average molecular weight that obtains the described polyalkylene glycol of described water-insoluble polyalkylene glycols multipolymer is more than 200, below 40,000.
12. Biodegradable particles as claimed in claim 7, is characterized in that, the weight-average molecular weight of the water-insoluble copolymer being made up of described water-soluble polymers and described Biodegradable polymer is 1,000～100,000.
13. Biodegradable particles as claimed in claim 1, is characterized in that, described Biodegradable particle is used to medical medical use.
14. Biodegradable particles as claimed in claim 1, is characterized in that, described Biodegradable particle is used as intracorporeal indwelling utensil.
15. Biodegradable particles as claimed in claim 14, is characterized in that, described Biodegradable particle is used to embolotherapy.
CN201110265699.0A 2005-10-27 2006-10-26 Biodegradable particle Expired - Fee Related CN102432986B (en)

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